Throughout this application various publications are referenced and citations are provided in parentheses for them. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
Steroids, particularly 5-alpha-steroids and 4,5 dehydro analogs thereof, are well known chemical compounds which exhibit significant physiological activity. Steroids having a keto group at the 3-position are especially important in this regard. 5-alpha-steroids of the androstane series are presently utilized as anabolic agents and fertility control drugs and as intermediates in the preparation of such agents and drugs. Certain steroids of the pregnane series are particularly effective as anti-inflammatory agents and as cardenolides. Steroids of the cholestane series, such as cholesterol and sitosterols, particularly beta-sitosterol, are naturally occurring compounds and are already useful or are potentially useful as starting materials for te commercial preparation of therapeutically important steroids.
Steroids which include a wide variety of substituent groups are useful therapeutically. For example, 9-alpha-fluoro substituted steroids and 16-alpha-methyl substituted steroids, such as 9-alpha-fluoroprednisolone, triamcinolone, 16-alpha-methylprednisolone, and dexamethasone, exhibit high glucocorticoid and anti-inflammatory activity. (U.S. Pat. Nos. 2,864,836 [1958] and 2,838,547 [1958]; and generally L. F. Fieser and M. Fieser, STEROIDS, Van Nostrand Reinhold Co. [1959], pp. 682-696). In the androstane series, 11-beta-hydroxyl substituted compounds which have antiandrogenic and gonadotropic activity have been described (U.S. Pat. Nos. 2,732,479 [1956] and 2,702,811 [1955]). Those skilled in the art to which this invention pertains will know other compounds characterized by the basic sterioid nucleus which may be utilized either directly as, or indirectly to provide, useful compounds.
Synthetic procedures are known for the production of useful steroids from naturally occurring steroids. Diosgenin is an important source of steroids of the pregnane series such as prednisolone and its numerous derivatives. Because of their ready availability from plant sources, sitosterols, particularly beta-sitosterol, have been often studied as commercially useful starting materials for the synthesis of 5-alpha-steroids of the pregnane and androstane series. However such approaches have not met with significant success, principally because of difficulties in removing the side chain, except in low yield, and in introducing functional groups into a molecule devoid of such groups other than the 3-beta-hydroxy group and the double bond at the 5,6 position.
Available methods for removing the side chain include chemical and microbiological oxidation. Unfortunately, the yields from these procedures are unacceptably low. Moverover, a significant capital investment is required to construct, operate and maintain a plant to carry out microbiological oxidation.
Methods have previously been developed to direct chlorination to various tertiary positions on steroids by the use of attached iodine-- or sulfur-- containing templates. The resulting chlorinated steroids may then be used as precusors to introduce double bonds or other functional groups at the chlorinated site. (Breslow, R., Corcoran, R. J., and Snider, B. B., J. Am. Chem. Soc. 1974, 96: 6791; Breslow, R., Corcoran, R. J., Snider, B. B., Doll, R. J., Khanna, P. L. and Kaleya, R., J. Am. Chem. Soc. 1977, 99: 905; Breslow, R., Wife, R. L. and Prezant, D., Tetrahedron Letters 1976, 23: 1925; and Breslow, R. and Heyer, D., J. Am. Chem. Soc. 1982, 104: 2045).
In Breslow et al., U.S. Pat. No. 4,252,719 (1981), a method for the selective removal of tertiary hydrogen atoms on steroid nuclei and side chains is described. This method requires that the steroid be esterified by iodo aryl substituted acids, acid anhydrides, or acid chlorides, thereby covalently binding a iodo aryl template compound being covalently bound to the steroid. Breslow et al., U.S. Pat. No. 4,323,512 (1982), discloses an improvement on this method so as to directly esterify the 17-alpha-hydroxy group of a steroid to form the covalently bound iodo aryl template compound.
Once the template is attached, the steroid esters is then chlorinated under free radical generating conditions in order to selectively replace the hydrogen with a chlorine. The chlorinated steroid ester is thereafter dehydrochlorinated to produce the unsaturated steroid.
An iodo aryl template which halogenates three steroid substrates has also been described. Breslow, R. and Heyer, D., J. Am. Chem. Soc. 1982, 104: 2045.
The present invention provides a method for substituting a chlorine atom for a hydrogen atom on a steroid nucleus by using a template compound comprising a pyridine ring or a substituted or fused ring derivative thereof. The template compound of the present invention possesses several advantages over the above-described templates containing an iodaryl or sulfur aryl group. For example, nicotinic acid, which may be used as a starting material for the template compound, is part of the natural vitamin niacin, and therefore, harmless if ingested as a contaminate in the end-resulting medicinal products. Moreover, the geometry of the chlorine atom adduct of a pyridine compound is expected to be different than the geometry of the chlorine atom adduct of iodo aryl compounds. Therefore, selectivities of the two adducts are expected to be different. Pyridine compounds are also basic, while the iodo and sulfur-containing templates are not. Thus, pyridine templates may be removed and recovered by extraction with acid, while the previously known templates cannot. Additionally, pyridine derivatives are generally more available than are iodobenzene derivatives, thereby making pyridine-containing templates more economical.